Cell Biology and Genetics of T Cell Activation and Death A network of cytoplasmic proteins, originally described to mediate cell death, can assemble in different combinations and at different cellular locations to regulate several aspects of immunity. In response to 'Death Receptor' (DR) ligation a complex of Fadd, Tradd, Ripk1, and Caspase-8 assemble to form the 'Death inducing signaling complex' (Disc) that causes apoptotic cell death. In the absence of Caspase-8 activity, these same molecules along with Ripk3 can assemble to carry out a separate 'necroptotic' form of cell death. We propose that the absence of Caspase-8 is a molecular signature of viral infection, e. g., herpes family or pox family viruses, and as a counter defense, vertebrates have evolved a parallel pathway of cell death. Three fundamental concepts in immunology are addressed in this application. 1) How does Caspase-8 regulation of innate immunity in dendritic cells affect the magnitude and quality of the adaptive immune response? 2) How do different pathways of virally-induced cell death affect the course of disease, clearance of virus, and the differentiation of T cells? 3) What are the death pathways operative in the contraction of T cells and the resolution of an immune response following viral infection, how do these principles differ between persistent and acute viral infections? The approaches include a step-wise analysis of the innate and adaptive immune responses to viral infections in mice with selective mutations in the genes encoding Disc components. Understanding the biology underlying T cell expansion and cell death is important in designing new immunologically-based therapeutic strategies, especially for infectious agents mediating persistent viral infections. PUBLIC HEALTH RELEVANCE: One of the most important mechanisms of medical intervention relies on vaccination against infectious disease, yet for many persistent viral infections, an effective vaccine is not at hand. In particular, the evasion strategies of viruses often affect cellular suicide mechanisms necessary for an effective and well-regulated immune response. This proposal explores manner in which three different modes of cell death control the immune response to strategically selected viral infections.